Gonorrhea is the second most reported sexually transmitted disease in the United States. According to Centers for Disease Control and Prevention (CDC), an estimated 600,000 new infections occur each year (STD Treatment Guidelines, MMWR 2006). Neisseria gonorrhoeae typically infects multiple organs including urethra, cervix, rectum, pharynx, eyes, skin, and joints (Merck Manual) and causes morbidity in humans. Neisseria gonorrhoeae often cause painful inflammation and discharge. However, Neisseria gonorrhoeae infections can be asymptomatic. Asymptomatic, untreated, and under-treated infections can lead to more severe sequelae such as gonococcal disseminated infections, septic arthritis, and pelvic inflammatory disease (PID). PID can result in preterm labor, chronic pelvic pain, ectopic pregnancies, and sterility in women (CDC, 2003). Antibiotic treatment is the only viable option available today to alleviate the symptoms and cure the Neisseria gonorrhoeae infection, yet with declining efficacy.
In 1936, sulfanilamide was first antibiotic introduced to treat Neisseria gonorrhoeae in patients. The treatment was ineffective; in large part because of its short-lived efficacy due to rapid emergence of antibiotic resistance, i.e., chromosomal mutations and acquisition of mobile genetic elements from the environment (Workowski et al., 2008).
In 1945, penicillin emerged as a new antibiotic to replace sulfanilamide and since then it gained a wide-spread use in the treatment of gonorrhea. Alexander Fleming discovered penicillin on Sep. 28, 1928, and the penicillin structure was elucidated by Dorothy Crowfoot Hodgkin in 1945. Use of penicillin in the first patient with streptococcal septicemia has made a landmark on Mar. 14, 1942. Thereafter, penicillin has been commercially produced in large quantity. As of 1945, CDC recommended penicillin in the treatment of gonorrhea.
Over time, however, the efficacy of penicillin has notably undergone a progressive decline. Neisseria gonorrhoeae has gradually developed penicillin resistance, largely attributed to a series of cumulative chromosomal mutations in several genes (e.g., penA, ponA, penB and mtrR). Each new gene mutation cumulatively increases antibiotic resistance and increases the minimum inhibitory concentration (MIC) for penicillin. In response, CDC recommended an increasing dosage for penicillin (from 50,000 units in 1945 to 4.8 million units by the early 1970s) (Workowski et al., 2008).
Wide-spread and heavy use of penicillin continued to escalate over the years, so did the antibiotic resistance. In 1976, a mobile genetic element (i.e., plasmid) was identified that carries the bla gene (Ashford et al., 1976). The bla gene encodes penicillinase that enables the bacteria to degrade penicillin, leading to an exceedingly high level of penicillin resistance in Neisseria gonorrhoeae. In 1985, a new class of chemically modified penicillin (i.e., ceftriaxone), which possess the ability to resist penicillinase, was recommended by the CDC as an alternative treatment regimen for Neisseria gonorrhoeae. By 1989, CDC no longer recommended the clinical use of penicillin because of the widespread penicillin resistance.
In 1948, tetracycline is a large antibiotic family that was discovered by Benjamin Minge Duggar. In 1950, Harvard Professor Robert Woodward determined the chemical structure of a tetracycline member (terramycin). The non-β-lactam tetracycline emerged as an alternative antibiotic for gonorrhea. Like penicillin, tetracycline resistance soon developed in Neisseria gonorrhoeae after its wide-spread use. The antibiotic resistance mechanism also involves additive chromosomal mutations and plasmid transfer. In 1970-1980's, chromosomal mutations in three genes, mtrR, penB, and rpsJ, caused progressive tetracycline resistance (Hu et al., 2005). In 1983, a highly tetracycline resistant Neisseria gonorrhoeae clinical strain was isolated, harboring a plasmid containing the tet(M) gene (CDC, 1985).
In 1993, CDC recommended oral fluoroquinolones (e.g., ciprofloxacin, levofloxacin, and ofloxacin) as well as oral cephalosporin (e.g., cefixime) in Neisseria gonorrhoeae treatment. The emergence of quinolone-resistance was observed, again due to chromosomal mutations in the gyrA and parC genes of Neisseria gonorrhoeae. By 2000, fluoroquinolone resistant Neisseria gonorrhoeae was increasingly noted in patients who became infected in Asia, the Pacific Islands (including Hawaii), and California (San Francisco). In response, CDC no longer recommended fluoroquinolones as a treatment regime in Hawaii. The number of flouroquinolone resistant isolates continued to reach high numbers (>20%). Shortly thereafter, the CDC announced that fluoroquinolones were no longer recommended in other parts of the US.
Presently, CDC recommends only one class of antibiotic (i.e., cephalosporin) for Neisseria gonorrhoeae treatment. Ceftriaxone, a member of cephalosporins, is available as an intramuscular injection (125 mg) as the CDC recommended regimen for uncomplicated urogenital and anorectal infection. Cefixime, another member of cephalosporin, is available as an oral regimen (400 mg) as the CDC recommended regimen for gonorrhea treatment. Cephalosporins represent the last resort as the only currently CDC recommended antimicrobial class. It is critical that susceptibility profiles to this remaining class of drug be closely monitored. Unfortunately, recent reports from Japan and Western Pacific Region indicate the appearance of Neisseria gonorrhoeae that exhibits a decreased susceptibility to cephalosporins. The underlying mechanism seems to be related to the alterations in penA, mtrR, ponA, and penB (Lee et al., 2010). The emergence and dissemination of such decreased susceptible strains of Neisseria gonorrhoeae is of particular concern.
The trend of indiscriminate and over-use of a few antibiotics presents a bleak future. First, heavy use of a few remaining CDC recommended antibiotics hastens evolutionary pressure towards antibiotic resistance. Second, there have been little or no new antibiotics on the horizon invented by pharmaceutical companies indicated for Neisseria gonorrhoeae for many years. Accordingly, there remains a great demand for determining an antibiotic resistance profile in Neisseria gonorrhoeae, information of such profile is believed to be essential in the antibiotic treatment regime.